A phase 2, 104-week study of repeat lorecivivint injections evaluating safety, efficacy, and bone health utilizing quantitative computed tomography (qct) in knee osteoarthritis (oa-06)

Background Knee osteoarthritis (OA) is a common joint disorder associated with pain, disability, and damage. There is unmet need for safe and efficacious treatments for symptoms and structural modification. Lorecivivint (LOR), an intra-articular (IA) CLK/DYRK inhibitor thought to modulate Wnt and inflammatory pathways, is in development as a potential knee OA treatment. Objectives To assess the safety and tolerability of repeated 6-month dosing of LOR in a 104-week trial (OA-06, NCT03727022 ). Additionally, to characterize juxta-articular bone health with quantitative computed tomography (qCT) and regional bone health via dual energy x-ray absorptiometry (DXA). Methods Participants with ACR-defined clinical and radiographic knee OA, aged 40-80, and Kellgren-Lawrence (KL) grades 2-3 were randomized 1:1 to receive IA injections of 2 mL 0.07 mg LOR or vehicle PBO at baseline, 24, 52, 72 weeks. The trial was conducted in two 52-week phases, part A (baseline to week 52) and part B (week 53 to week 104), with part A completers invited into part B. Safety was assessed by collection of adverse events (AEs), and serious AEs (SAEs). Bone safety assessments included qCT to assess target and non-target knee BMD, DXA to assess spine and hip BMD and bone/ cartilage biomarkers. Exploratory efficacy was assessed by patient-reported outcomes (PROs). For bone imaging endpoints, change from baseline was estimated using baseline-adjusted ANCOVA. Results 101 participants (mean age 60.9±9.1 years, BMI 28.6±3.7 kg/m 2 , female 59.4%, KL2 52.5%) were enrolled. 77 participants completed part A and 53 completed part B. AE rates were similar between PBO and LOR, and no SAEs were deemed treatment related. There were no clinical bone health signals (no fractures, accelerated OA, osteoporosis) observed for LOR. Observed target knee qCT BMDs were similar between LOR and PBO (Figure 1). Change from baseline in BMD at Week 104 was -7.08 (12.34) mg/cm 3 in LOR and -2.95 (8.65) mg/cm 2 in PBO, (estimated difference -4.05 [95% CI -11.21, 3.11], not significant). Trends in target knee BMDs for those with higher risk of decreasing BMD, (female and age 65-80), showed no meaningful differences between LOR and PBO. There were no significant differences in total hip or spine BMD between LOR and PBO. Potential confounding factors included baseline imbalances in sex (PBO 68.0% vs. LOR 51.0% female), KL grade (PBO 62.0% vs LOR 42.1% KL 2), and site randomization. There were no meaningful differences in PRO changes between LOR and PBO groups. A trial conduct limitation was the small number of qCT-enabled sites available in the US. Conclusion The incidence of AEs was similar between treatment groups and not affected by repeated injections of LOR. Multiple injections of LOR over 2 years did not appear to lead to any bone health adverse effects locally around the knee or regionally at spine or hip. Table 1A and 1B. Phase A #Events/#Subjects Reporting Phase B #Events/#Subjects Reporting LOR (n=50) PBO (n=50) LOR (n=50) PBO (n=50) Adverse events 52/25 52/24 Adverse events 52/25 52/24 SAEs 5/2 3/2 SAEs 5/2 3/2 Target-knee AEs 7/6 4/3 Target-knee AEs 7/6 4/3 Figure 1. Total Target Knee BMD over 104 weeks REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests Yusuf Yazici Shareholder of: Biosplice Therapeutics, Employee of: Biosplice Therapeutics, Christopher Swearingen Shareholder of: Biosplice Therapeutics, Employee of: Biosplice Therapeutics, Heli Ghandehari Shareholder of: Biosplice Therapeutics, Employee of: Biosplice Therapeutics, Jon Britt Shareholder of: Biosplice Therapeutics, Employee of: Biosplice Therapeutics, Sarah Kennedy Shareholder of: Biosplice Therapeutics, Employee of: Biosplice Therapeutics, Jeymi Tambiah Shareholder of: Biosplice Therapeutics, Employee of: Biosplice Therapeutics, Nancy Lane Consultant of: Biosplice Therapeutics.